PT97977B - METHOD FOR PREPARING REVERSE GELIFICATION COMPOSITIONS, BASED ON TEMPERATURE SENSITIVE POLYMERES AND PH, FOR EXAMPLE METHYL CELLULOSE AND POLYACRYLATE - Google Patents

Abstract

Reversibly gelling aqueous and oil emulsions are disclosed which can be modified to incorporate oil soluble pharmaceutical compounds for delivery to physiological systems in a soluble form and which undergo significant changes in viscosity in response to substantially simultaneous changes in both temperature and pH. The compositions are formed of relatively low concentrations of a stable combination of at least one pH-sensitive reversibly gelling polymer, at least one temperature-sensitive reversibly gelling polymer and at least one organic oil. The compositions can be formulated to exhibit a sol-gel transition over a wide range of conditions and viscosities and may be modified to incorporate a pharmaceutical compound for utilization as droppable or injectable drug delivery systems which will gel following administration to a physiological system for the sustained delivery of such pharmaceutical compounds.

Description

DESCRIPTION MEMORY

Field of the Invention The present invention relates, in general, to mixtures of macromolecular polymers which reveal reversible gelling properties., More particularly, the present invention relates to aqueous compositions which reversibly gel in response to simultaneous variations by at least two parameters physical factors such as temperature and pH or ionic strength. These compositions can be prepared to reversibly geify at viscosities that vary in a relatively wide range of conditions, making them particularly suitable for use in delivery systems of: oral, injectable or drop drugs, for sustained and controlled distribution of pharmaceutical drugs and agents diagnostic ,,

Background of the Invention

Over time, several approaches have been developed to the production of reversible gelling solutions. Efforts have been primarily devoted to the development of subcutaneous gelatinous drug delivery systems for applications and, more recently, for topical and ophthalmic drug administration to the eyes. In general, sustained-release drug systems incorporate pharmaceutical agents in solid or semi-solid vehicles that are applied to the skin or implanted under the skin of a patient by medical personnel »In addition, unlike conventional drug delivery systems .

drug delivery systems to the eyes must also consider the additional problem of drug loss through the tear drainage system as well as the need to comfort the patient and facilitate administration.

Previous approaches to solving problems associated with drug delivery systems to the eyes used semi-solid ointments or gels applied directly to the conjunctiva or the corner of the eye to retain the pharmaceutical agents contained therein on the surface of the eye, as opposed to physiological factors. like the overflow of tears.

698

16813 (AP) -Portugal

tears running down the tear duct, blinking and other mechanical losses. For example, US patents No. 3 944 427 and 3 700 451 describe gelatinous drug delivery compositions containing agar, xanthan gum and locust bean gum in liquid media to increase their residence time on the skin or mucous membranes and the consequent bioavailability of the medicinal products contained therein. Similarly, European Patent Application NS 0 300 888 A1, filed on July 18, 1988, recently revealed the use of rhamsan gum to spess ophthalmic compositions for drops and topical application.

Although effective in increasing the drug retention time, the lack of acceptability by the patient remains a significant disadvantage in the use of such already known compositions for applying viscous drugs to the eyes. Many patients find it difficult to apply the appropriate amount of these drugs to their eyes and are opposed to the unpleasant side effects of accumulations in the eyelid and visual impairment of vision. As a result, these compounds are only suitable for use at night or during hours of inactivity.

A known alternative approach to these problems was the use of a formulation that is liquid at room temperature but that becomes semi-solid when heated to body temperature. This temperature-actuated system is described in U.S. Patent No. 4,474,751 where an aqueous drug delivery system that forms a semi-soluble gel at body temperature, and prepared from patented polymers known as Tetronic® polyols In general, these compositions are prepared from about 10% to 50% of specific polymers in an aqueous base. By adjusting the pH of these drug delivery systems, by adding buffering agents, the gelling transition temperature can be increased to physiological temperatures in the order of 35 ° C.

US Patent No. 4,474,752 describes similar drug delivery systems that can be injected

472 '698 χ 6 β 1 · 3 (Α Ρ) - ο ο r t u g a 1 subcutaneously or intramuscularly. These compounds also contain 10% to 50% by weight of Tetronic® polymers and gel at temperatures between about 30 ° to 10X.

A distribution system for drugs that gel by thermal fixation is also described in. US patent NS 4 188 373 which uses Pluroriic © polishes as the thermally gelling polymer. By adjusting the concentration of the polymer, the desired sol-gel transition temperature is obtained.

However, the production of a compound that gels in physiologically useful temperature ranges, limits the available viscosity of the gel product.

Alternatively, it has been proposed to use formulations that gel in response to changes in pH as drug delivery vehicles. By carefully controlling the pH of these mixtures, one could theoretically produce a solution that would form a gel after mixing with the aqueous tear fluid. However, it is believed that the relatively high buffering capacity of these pH-responsive compositions can lead to slow gelation, irritation and lack of comfort for the patient's eyes.,

Although they have been successful in obtaining longer drug retention times, the relatively high concentrations of polymers, necessary for these formulations, undesirably increase the buffering capacity and the amount of thermal energy necessary to induce the gelation of the compounds, which can cause irritation and discomfort when used in the eyes. Furthermore, high concentrations of polymers can also contribute to unacceptably high costs and, in general, delay the gelation process, causing the migration of compounds from the application or injection site.

Thus, it is a main object of the present invention to provide a polymer solution, of reversible gelation, having significantly lower polymer concentrations

696

16813 (AP ') -Portugal

ísíSj than those that could be obtained in the prior art, in order to reduce the buffering and thermal capacities of the solution to ensure its rapid and complete transition from liquid to gel, after application to a physiological system such as an oral dosage , an application to the surface of the eye, or a drug deposit 1 n 3 ec tá ve 1 ..

It is also an object of the present invention to provide a reversible geiification solution that can be used as a drug delivery vehicle or wetting solution that can be easily administered by the patient, in the form of a free-flowing liquid or drops, which immediately gel. after administration, with minimal side effects, thus providing the patient with easy control of the drug dosage and better patient acceptability.

It is also an object of the present invention to provide a drug delivery vehicle, oral dosage »instillation of drops, injectables or in deposit form» that prolongs the contact time of the drug, for better bioavailability and for sustained drug release »

Summary of the Invention

In general terms, the present invention achieves the objectives described above by preparing aqueous compositions that gel reversibly in response to substantially simultaneous variations in at least two physical parameters, such as temperature, pH or ionic strength. Furthermore, the compositions of the present solution specific gel a temperature

a transj Lesson gamma of pH ass 1st rmen te good instillation per

drops and as drug delivery systems, as well as for use as sustained release injecting drug delivery systems »

More particularly, it has surprisingly been found that reversible gel compositions can be prepared

698

1.6 8 X 3 (A Ρ) - t ο r t u g a i

higher, from unusually low concentrations of remarkably synergistic polymer systems, stable in aqueous solutions. In contrast to the prior art gelling systems which rely solely on a single triggering mechanism, which may be a change in pH, or ionic strength or temperature, the compositions of the present Invention gel reversibly in response to substantially simultaneous variations in both . temperature and pH in predetermined ranges. Furthermore, the synergistic gelling action of the compositions of the present invention produces rapid & complete variations in viscosity of a certain order of magnitude without the side effects of concentration in polymers and prior art., Desirable to be associated with the simple mechanism of gelling

These properties make the compositions of the present invention particularly suitable for the use of topically applied lubricants © wetting agents as well as for drug delivery vehicles where a sustained and controlled release of the biochemical agents is desired. For example, according to the conclusions of the present invention, wetting agents can be produced.

ophthalmic drug delivery vehicles, oral and injectable drug delivery compositions, which exhibit steady-state flow characteristics at or near room temperature and a pH range of 2.5 to 6.5, even if it changes, almost instantly , in highly viscoelastic gels when exposed to physiological pH and temperature conditions of the order of pH 7.4 and 37 * 0.

Teaching compositions of the present invention are prepared, containing effective concentrations of a combination of at least one temperature sensitive gelling polymer and at least one pH sensitive gelling polymer. The temperature-sensitive gelling polymers for the practice of the present invention can be a group consisting of alkyl cellulose, cellulose ethers, Pluronic ^K polymers chosen from those of hydroxyalkyl cellulose, and Tetronic ^R polymers.

example, according to those from aqueous solutions, a stable physical mixture or .16813 ί AP) -Po rtuga I

with methyl cellulose being particularly preferred »preferred polymers with gelation triggered by pH, which produce thickening at a pH increase, acidic polymers such as those containing carboxyl groups» Those skilled in the art know that small amounts of crosslinking agents, such as divinylbenzene, divinylglycol © polyalkenylpolyethers facilitate the formation of polymers with three-dimensional lattice structures in the resulting cross-linked polyacrylates »Examples of these acidic, pH-sensitive gelling polymers are the linear or branched or cross-linked carboxyvinyl polymers or monomers such as monomers methacrylic, ethacrylic acid, β-methylacrylic acid, cis-a-methylcrotonic acid, etc. trans-a-methycrotonic acid, α-butycrotonic acid, x-phenylacrylic acid, α-benzylacrylic acid, α-benzylacrylic acid, tx-cyclohexylic acid and the like ,. conversely, when a thickening at a pH reduction is desired, polymers containing weakly basic groups such as poly-N-N-dimethylamethylethanol and tachymethyl may be used.,

In contrast to the relatively high concentrations of polymers required by the individually acted compositions of the prior art (of the order of 10% or more by weight), the reversible gelling compositions of the present invention preferably contain only about 0.25% up to 5% by weight of temperature-sensitive gelling polymer and only 0.1% to 0.5% of pH-sensitive gelling polymer „This substantially lower concentration of polymer significantly reduces the amount of energy .....

thermal energy needed to induce gelation as well as reduce the buffering capacity of the compositions of the present invention, making them topically wetting agents and drug delivery compounds, markedly better »When used in ophthalmic media, the compositions of the present invention eliminate discomfort, the fogging of vision and deposits produced by compositions already known from the prior art even though they produce rapid conformational changes at high viscosity.

However, it is considered to be within the scope of the present invention to use concentrations of gel polymers.

temperature sensitive, ranging from about 0.1% to 30% by weight and concentrations of pH-sensitive geiification polymers, ranging from about 0.01% to 10% by weight- As discussed below in detail, these relatively wide polymer concentration ranges increase the scope of the available viscosities and the so-gel transition temperatures that can be produced according to the studies of the present invention. Thus, with the present invention, they can be obtained viscosities ranging from 200 to about 1 million cP, at sol-gel transition temperatures ranging from 0C to 6O '' 'C „However, for the ophthalmic uses, the polymer concentration ranges described above are preferred.

The compositions of the present invention, for use as drug delivery vehicles, can be modified by incorporating a pharmaceutically suitable medicament or diagnostic compound, in a concentration ranging from about 0.0001% to 50% by weight. Those of skill in the art know that when ss incorporate compatible drugs and / or diagnostic compounds in the aqueous compositions of the present invention, the drugs will also be incorporated into the gelling matrix after placement at the application site. As a result, the visco-elastic gel containing the drug will be present at the application site, thereby prolonging the retention and release of the incorporated drug. Similarly, delivery systems, containing the drug in particles or in fine suspensions of solid drug compositions, can also be incorporated into the reversible gelation compositions of the present invention. Injection into subcutaneous drug delivery tanks or topical delivery by instillation of solutions will position these delivery systems in the location chosen for sustained bioavailability. This greater bioavailability and longer duration of action allows for lower overall drug doses resulting in a better side effect profile.

In the compositions of the present invention, changes in viscosity ranges, pH ranges and temperatures, to which the sol-gel transition occurs, can be produced by varying

the concentrations of the polymer or incorporating small amounts of univalent or divalent salts. Typically, the addition of small amounts <combined, up to 0.5 e.

and salt that gives preference to the prορ o rtion s ai / polymere, in the order of 0.045 to

0.075 will lower the viscosity of the composition in the non-gelled state, if desired. Alternatively, it is considered within the scope of the present invention to incorporate from about 0.2% to 0.9% by weight of leaves.

Other objects and advantages of the reversible gelling compositions of the present invention, as well as their better understanding, will be provided to those skilled in the art, after considering the following detailed explanation of the examples of their preferred embodiments. Reference will be made to the attached sheets of the drawings, now briefly described „

Brief Description of Drawings

FIG. I is a graphic illustration showing the viscosity of a Methocel / Carbopol mixture (the Carbopol concentration was fixed at 0.3% by weight) as a function of. concentration of Methocel, at room temperature and pH 4.0 of Carbopol;

FIG. 2 is a graphic illustration showing the viscosity of a Methocel / Carbopol mixture (the concentration of Carbopol fixed at 0.3% by weight) as a function of the concentration of Methocel at 37 ° C and pH 7.4 of Carbopol :;

FIG. 3 is a graphical illustration showing the viscosity of a Methocel (1%) / Carbopol (0.3%) mixture as a function of the salt concentration, at room temperature and pH 4.0;

FIG. 4 and a graphic illustration showing the viscosity of a mixture

Methocel (1%) / Carbopol (0.3%) as a function of the salt concentration at 37 ° C and pH 7.4;

FIG. 5 is a graphic illustration showing a Pluronic / Carbopol mixture (0.3 wt% concentration) as a function of the Carbopol concentration at room temperature and pH 5.0;

FIG. 6 is a graphic illustration showing a mixture of Pluroni ^ S ^ Oarbopol (concentration of the viscosity Carbopol fide Pluroriic ^R â.

viscosity

Cargopol fixed it

698

16813 (AP) -Portugal gives 0.3% by weight) as a function of Pluroníc © concentration at 37 ° C and pH 7.4 of Carbopol;

Flfâ »7 is a graphic illustration showing the viscosity of a Tetronicí / Carbopol mixture (Cargopol concentration fixed at 0.3% by weight) as a function of. concentration of Tetronic® at room temperature and pH 5.0 of Carbopol; and Figure '8 is a graphical illustration showing the viscosity of a mixture of TetronicP ^ / Carbopol (Cargopol concentration fixed at 0.3% by weight) as a function of concentration Tetronicí® at 37 ° C and pH 7 ^3, 4 from Carbopol »

Detailed Description of Preferred Embodiments

The aqueous reversible gelling compositions of the present invention are primarily intended for use as delivery vehicles for instillable, oral and irritable drops as well as for topical application of lubricants, wetting agents and cleaning agents. Thus, the preferred embodiments for example of the present invention show good flow characteristics at room temperature, even though they quickly gel in viscoelastic compounds, exhibiting viscosities of several orders of magnitude higher at physiological temperatures and pH »Thus, the preferred embodiments for example, they show significant increases in viscosity in response to substantially simultaneous increases in temperature and pH for conditions found in the ocular environment or in the local injection drug application sites. However, those skilled in the art know that alternative compositions can be produced that gel in response to simultaneous increases in temperature with decreases in pH, or the reverse, according to the teachings of the present invention, whenever desired. Similarly, alternative compositions can also be produced that gel at temperatures significantly above or below those found in physiological systems or that show viscosities distinctly different from those used by preferred embodiments »Thus, for the purpose of better understanding, and without limiting the Within the scope of the present invention, the following example embodiments will be discussed in the context of reversible gelling compounds

698 l6 813 (Α Ρ) - Also for 1

-ll

injectable or with unstable drops, intended for use in physiological systems.

As those skilled in the art will understand, in addition to responding to simultaneous variations in temperature and pH, the ability to produce intense, viscosity variations with very low concentrations of polymers, and a significant feature of the present invention that overcomes many of the disadvantages associated with compositions of prior art. For example, the polymer concentrations used in accordance with the teachings of the present invention significantly reduce the buffering capacity of the aqueous compositions thus produced, thus effectively eliminating the irritation associated with compounds with high buffering capacity, such as pH-acting gelation compositions. , of the prior art. Similarly, reducing the concentration of polymers also reduces the thermal energy requirement of the compositions of reversible gelation compositions, as a result of which those of the present invention gel almost instantaneously after application. This instantaneous gelation further reduces the migration and loss of the compositions of the present invention, in relation to the compounds of the prior art. As an added benefit, the low-polymer compositions of the present invention produce clear and colorless gels, making them particularly well suited for their use as ophthalmic drug delivery vehicles.,

In its broadest capacity, an example embodiment of the aqueous compositions of the present invention, which exhibits reversible gelation in response to simultaneous variations in both temperature and pH in predetermined zones, comprises an aqueous solution incorporating a stable combination or a hair mixture. at least one thermosensitive gelation polymer and at least one pH sensitive gelation polymer, in sufficient quantities to effectively produce a reversible gelation in the desired temperature and pH ranges. Preferred temperature-sensitive gelling polymers include alkyl cellulose, hydroxyalkyl cellulose, cellulosic ethers, polymers and Tetronic® polymers, methyl cellulose being

698

813 {. A P) ~ Portugal

particularly preferred »The preferred pH-sensitive gelling polymers, which increase viscosity with increasing pH, are chosen from the family of linear, branched or cross-linked acidic polymers, such as those containing carboxyl groups, particularly carboxy-vinyl polymers of monomers such as acrylates, methacrylic acid, ethacrylic acid, methyl methyl acid, cis-alpha-methyl acid, trans-alpha-methylcrotonic acid, α-butyl-crotonic acid, α-phenylacrylic acid , α-benzylacrylic acid, α-cico-hexi1acrylic acid and the like »Examples of concentrations that give the widest range of viscosities and sol-gel transition temperatures of about 0.1% to 40% by weight, of polymer of temperature sensitive gelation is from about 0.01% to 10% by weight of pH sensitive gelation polymer. For physiological systems, the preferred example concentrations that give the preferred soi-gel transition temperatures and preferred associated viscosities, range from about 0.1% to 5% by weight of temperature sensitive gelation polymer, and about 0.01% to 0.5% by weight of pH sensitive gelation polymer „

To the west, an example composition of the present invention comprises a complex homogeneous combination of a macromolecular mixture of methyl cellulose, a polysaccharide marketed by Dow Chemical under the trademark Methocel, and a cross-linked polyacrylic acid such as Carbopol 940, a hydrophilic acrylic polymer marketed by 8, F. Goodrich Company, ú

Methocel consists of cellulose chains with a moderate to high degree of substitution for the hydrophobic methyl group, while Carbopol is a hydrophobic acrylic polymer made up of 0.1% to 10% by weight of Methocel, one obtains one of polymers. This the teachings of art

When these polymers are mixed in the preferred ones, for example, ranging from 0.01% to 30% by weight of the stable combination of the aqueous mixture, the result is in direct contrast to the previous molecular difficulties where the aqueous polymer mixtures are extremely if not impossible, to form due to interaction and precipitation .. Even more important, varying

698

16813 (AP) -Portugal

-13th range of concentrations of this composition a wide range of viscosities and sol-gel transition.

temperatures and pH of

For example, under various conditions of formation, the pH of the composition generally varies between approximately 2.5 and 6.5, with a preferable range of 4.0 to 5.5. Osmolality varies from 20 to 500, preferably from approximately 50 to 400 „Osmolality can be adjusted by adding physiologically acceptable salts and non-ionic additives such as sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium lactate, magnesium phosphate, mannitol, sucrose and glycerin. However, sodium chloride is the preferred tonicity adjuster. More significantly, at temperatures ranging from 0 ° C to 45 ° C and preferably between 15 ^φ 8 and 30 ° C, the viscosity of the composition can be adjusted to vary between 20 and 40 000 cP (measured at a rate of 2.6 s ^{-1 cut} ), with a preferred range of 100 to 30,000 cP to produce an injectable or drop-instillate viscous fluid. Taking these same formulations and exposing them to physiological conditions of a pH of about 7.4 and a temperature of about 37 ^O C, viscosities of 200 to 1 million cP result with a preferable zone of about 50 000 to 400 000 cP . As a result, the compositions of the present invention can be regulated so as to produce wetting agents, cleaning agents or delivery systems for ophthalmic drug instillations in drops that will remain in the eye from fractions of an hour to 10 hours or more, and preferably from two to six hours.

More specifically, when concentrations of about 1% to 3% by weight of methyl cellulose and 0.2% to 0.4% by weight of Carbopol are mixed in the example aqueous compositions, one forms. stable combination of. aqueous polymer mixture that has a viscosity of the order of 10,000 cP at room temperature (25 ° C) and a pH of 3.0 to 5.0. When this composition is subjected to physiological temperatures and pH, of the order of 37 ”C and pH 7.4, it is believed that two simultaneous intermolecular conformational changes occur. First, the increase in ionization

698

16813 (AP) -Portugal

í.

produces the opening of the spirals of the acrylic chain. This is accompanied by the expulsion of the hydrophobic functional components from the methyl cellulose chain. As a result, within approximately 60 to 120 seconds a three-dimensional network is formed with a concomitant increase in visco-elasticity, of various orders of magnitude, up to approximately 140,000 cP. Experts in the art know that distribution vehicles compatible medicines, diagnostic compounds and drugs in microfine particles, incorporated in the composition, will be retained in the matrix of the visco-elastic polymer thus produced, for sustained release applications when desired, as these significant viscosity increases occur with as much low concentrations of polymers in response to simultaneous variations in temperature and pH, is in complete contrast to the teachings of the prior art. As mentioned above, systems of the prior art for which a high variation in viscosity is induced only by variation in temperature, require preparations with high concentrations of polymers, typically much greater than 10% by weight, Airida plus, with these high concentrations , the limitations of heat transfer of the preparations themselves can lead to relatively slow or incomplete viscosity increases »In addition, high concentrations of polymers in the prior art can cause discomfort, clumps of polymers on the eyelids, blurred vision and altered anatomical states as the blockage of lacrimal caries. Similarly, systems in which the change in viscosity is induced only by changes in pH, typically require high concentrations in polymers. These systems actuated by pH show a significantly higher buffering capacity than in those actuated by temperature. In the ocular environment, this high buffering capacity can lead to incomplete gelation and local irritation. Thus, the compositions of the present invention are significantly more advantageous than these systems already known, in two main aspects »First, when used in physiological states, the compositions of the present invention can

698

16813 (AP) -Portu ga1

-15 have a significantly lower total polymer content; and, second, these compositions effectively use the buffering and heating capabilities of the ocular medium to quickly and completely induce conformation variations that lead to substantially higher viscosity »aqueous compositions of the unexpectedly synergistic»

With the compositions of the present invention in general, the rheological properties of the example aqueous solutions, of temperature sensitive methyl cellulose and of pH sensitive polyacrylate, are obtained by the molecular masses of the respective polymers, by their concentration, temperature and the presence of other solutes »It should, however, be noted that the properties of the present invention are unique and, for example, because methylcellulose is non-ionic, alone in solution it is visco-elastic in a wide range of pH, from about 3 to 1.1 »The viscosity of the polyacrylate solutions, alone, is proportional to the concentration of the polymer, both at the lowest and the highest pH. For example, at polymer concentrations between 0.1% and 0.4% by weight, aqueous polyacrylate solutions are very low viscous in a pH range of 3 7 »In addition, aqueous solutions containing more than 0.5% in polyacrylate weights have a much higher buffering capacity and require an additional neutralizing base to increase their viscosity. However, mixtures of these pH and temperature sensitive polymers, according to the teachings of the present invention, show viscosities substantially at excess in relation to the sum of the individual viscosities of the aqueous solutions of individual polymers, tarite at low pH as high »For example, at pH 4.0, the viscosity of a 3% methylcellulose solution; in weight, measured by a Carri-Med rheometer, at a cut rate of about 2.6 s ”· ^, is approximately 18 000 cP„

Similarly, the viscosity of a 0.2% Carbopol solution at pH 4.0 is approximately 50 cP. The viscosity of the mixture of these two polymers, prepared according to the teachings of the present invention, at pH 4.0, is approximately 30,000 cP »Those skilled in the art will appreciate that 30,000 cP is substantially more than the predicted combined viscosity of 18,050 cP»

698

813 (AP) -Portugal

F ......

- '., «JÍl.

d6 ^M

The following Table is a list to illustrate the rheological properties that can be expected with the aqueous compositions of the present invention, using an example formulation, of Methocel A4M methyl cellulose and Carbopol (940), a cross-linked polyacrylate.

Table 1

Viscosity for a Typical Preparation of Methocel (1% by weight) / Carbopol (0.3¾ by weight) temperature 2.5 / c pH 4.0

V cosscosity, cP 11,500

37.X

4.0 7.4

20,000 140,000 / y 4

90,800 (cut rate, approximately 2.6 s ι

WIRES 1 and 2 show more clearly the rheological properties of example mixtures, Methocel / Carbopol, in accordance with the teachings of the present invention. As shown in FIGS. 1 and 2, the viscosity of an example aqueous composition, Methocel / Carbopol, is plotted as a function of the concentration of Methocel (the concentration of Carbopol being set at 0.3% by weight) at room temperature and pH 4 at FIG. 1, and at 37'C and pH 7.4 in FIG. 2. As shown in FIG. 1, aqueous compositions with a viscosity ranging from about 20 to more than 40,000 cP can be prepared at room temperature and pH 4, which, as shown in FIG. 2 „gel at viscosities ranging from about 200 to well over 200 000 under physiological conditions. As the experts in the art know, the previous temperatures and pH, mentioned in Table 1, are also an example of the conditions existing at room temperature (25 ° C) and in the ocular environment where the corner of the eye is bathed by isotonic tear fluid at pH 7.4 and approximately at 37 X. it was thus evident that the example composition described in Table 1 is that of a viscous liquid that flows freely at the temperature and pH of its formulation and that, after contact with the tear fluid and under conditions physiological, constitutes a highly visco-elastic gel.

In addition, highly visco-elastic gels, formed

698

16813 (AP) -Po rtu ga1

Physiological temperature and pH are transparent with a density of approximately 1.01 and a refractive index of about 1.33. In this way, the aqueous compositions of the present invention can easily be applied to the eye under the form of drops that will quickly geiify, when placed in the eye, under the combined effect of temperature and pH, thus avoiding its rapid elimination from the eye by the .lacrymal drainage system. In addition, the favorable optical properties and the low concentration of polymers in the compositions, should cause little or no visual disturbance, once frozen in ......... situ,

Note also that these example compositions, once gelled, show mucous-adhesive properties that further aid their retention in the corner of the eye. The gelled polymers are still self-lubricating, reactively smooth and deformable, which increases comfort and patient acceptability,

As shown in FIOS, 3 and 4, it should also be noted that the viscosity of the aqueous compositions of the present invention can be modified by the addition of a pharmaceutically acceptable salt, such as mono- or divalent salts including sodium chloride, o potassium chloride, calcium chloride or mixtures thereof, as well as suitable alkali metal salts such as sodium sulfate and the like. Preferred proportions of total salt / polymer range from 0 to about 0.5 and preferably from about 0.045 to 0.075. As shown in FIGS, 3 and 4, the addition of salts shows a more significant relative effect in the low range viscosities of the aqueous system. For example, slight increases in salt concentration apparently preferentially reduce the range of low viscosities, while showing a comparatively minor reduction in the range of high viscosities.

In FIGS 5 to 8 the rheological properties of the alternative example compositions produced according to the studies of the present invention are illustrated. FIGS 5 and 6 illustrate the viscosity of a Pluronic mixture prepared according to the teachings of the present invention. Pluronic polymers are block copolymers of propylene oxide and ethylene oxide, and are temperature sensitive gelation polymers. , Consíde & Ο

Ο? U ι6813 (AP) -Portugal

Within the scope of the present invention, the preparation of reversible gelling compositions comprising stable mixtures of 0.01% to 10% by weight of pH sensitive gel polymers, such as Carbopol, and from about 1% to 30% by weight of Pluroni ^ ® polymer. As shown in FIGS 5 and 6, these mixtures form viscous liquids at room temperature and pH and quickly gel into highly viscous-elastic gels under physical conditions.

Similarly, alternative compositions can be formulated, within the scope of the present invention, using Tetronic® polymers. Tetronic® polymers are bi-tetrafunctional copolymers, derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine. As shown in FIGS 7 and S, aqueous reversible gelation compositions can also be formulated according to the teachings of the present invention, using Tetronic® polymers in order to remain liquid at room temperature and low pH, in the order of 4.0 to 5.5, and to gel, under physiological conditions, in highly viscoelastic gels., Note that these alternative polymer compositions extend the temperature range available for gelation and formulation, without significantly altering pH conditions and osmolality, associated with these compositions.

Although the previous compositions, given by way of example, all gel reversibly in response to the simultaneous rise in temperature and pH, it is also possible to use the teachings of the present invention to produce aqueous compositions that are liquid at higher pH and at lower temperatures. low and that gel at lower pH (neutral or lower) and at higher temperatures. For example, polymers containing basic fracamerite side groups, such as polymers of po1ί-N, Nd i met i1-ami noet i1- methacrylate, which contains amines, can be combined with methyl cellulose, with Pluronic® or Tetronic® polymers or combinations thereof. These combinations will be liquid at a high pH and will geify at a lower pH at lower temperatures and higher temperatures.

? ζ ο να

16813 (AP) -Portugal

-19 Those skilled in the art will appreciate that the aqueous compositions of the present invention can be used as wetting or lubricating agents for contact lenses or for treating conditions such as dry eyes. It is preferred, however, that the compositions are used as drug delivery vehicles, for administering a variety of pharmaceutical drugs and diagnostic compounds.

The most promising drugs to be incorporated into the aqueous drug delivery compositions of the present invention are levobunolol, pilocarpine, dipivephrine, and others that show poor bioavailability. Other examples of drugs or diagnostic agents that can be administered by the aqueous compositions of the present invention include, but are not limited to:

(1) antibacterial substances such as beta-lactam antibiotics, cefoxitin, n-formamidoyl-thienamycin and other derivatives of thienamycin, tetracyclines, chloramphenicol, neomycin, carbenicillin, colistin, penicillin 0, polymyxin B, vancomycin, cefazolin, cheforzine, cheforzine, chefalin, chefalin, chefalin, chefalin, chefalin, chefalin, chefalin, chefalin, chefalin, chefalin, cefalin gramicidin, bacitracin, sulfonamides; amino-glycoside antibiotics such as gentamicin, kanamycin, amikacin, sisomycin and tobramycin; nalidixic acid and analogs such as norfloxacin and the antimicrobial combination of flucalamine / pentizidone; nitrofurazones and the like.

(2) antihistamines and decongestants such as pyrilamine, clopheniramine, tetrahydrazoline, antazonline and the like;

(3) 'anti-inflammatory drugs such as cortisone, hydrocortisone, hydrocortisone acetate, betamethasone, dexamethasone, dexamethasone phosphate and sodium, prednisone, methIprednisoione, medrisone, fluorometolone, fluocortolone, prednisolone, prednisolone, trisolone, sulphatone and trisolone, trisolone, trisoline, and , its corresponding salts and sulphides, and the like;

(4) miotics and anticholinergics such as ecothiophate, pilocarpine, fisost igm ina-salic i1ate, d ii sop rop i1f1u orophosphate, epinephrine, dipivoli1-epinephrine, neostigmine, ecothiophate iodide, demecoline bromide, carbacol, betacol, betacol, carbacol, carbacol similar:

698

813 (. A Ρ) -Portugal

(5) hydric drugs such as atropine, homatropin, lamina scope, hydroxy-amphetamine, ephedrine, cocaine, tropicamide, phenylephrine, cyclopentolate, oxiferion, eucatropine and the like; and other drugs used to treat eye conditions and diseases, such as (6) anti-glaucoma drugs, for example, betaxalol, pilocarpine, timolol, especially as maleate salt, such as R-timolol and as a combination of timolol or R -timolol with pilocarpine. Also included are epinephrine and the epinephrine complex, or prodrugs such as bitartrate, borate, hydrochloride and dipivephrine derivatives and hyperosmotic agents such as glycerol, rnariitol and urea;

(7) anti-parasitic compounds and / or anti-protozoan compounds such as ivermectin; pyrimethamine, tri-sulfapyrimidine, clindamycin and corticosteroid preparations;

(8) effective anti-viral compounds such as acyclovir, 5-iodo-2 ³ -deoxyuridine (IDU), adenosine arabinoside (ARA-A), trifluorothymidine, interferon or interferon inducing agents such as Poly I sC;

carbonic anhydrous inhibitors such as acetazolamide.

dichlorphenamide, 2- (p-hydroxyphenylJio-5-thiophene-sulfonamide, 6

-hydroxy-2-benzothiazo 1 o-su 1 fonamide and 6-pivaioioxy-2-berizothiazolo-sulfonamide;

(10) anti-fungal agents such as amphotericin B, nystatin, flucytosine, natamycin and miconazole;

(11) anesthetic agents such as cocaine ethydocaine, hyphenoxinate, dibucaine hydrochloride, diclonine hydrochloride, naepaine, phenacaine hydrochloride, piperocaine, proparacaine hydrochloride, tetracaine hydrochloride, hexilocaine, lidocaine, privacaine, lidocaine, privacaine, lidocaine, privacaine, lidocaine, privacaine, lidocaine, privacaine, lidocaine, privacaine, lidocaine, privacaine, lidocaine, privacaine, lidocaine, privacaine, lidocaine, privacaine, lidocaine, privacaine;

(12) ophthalmic diagnostic agents such as (a) those used to examine the retina and sodium dio-flucrescein chloride;

(b) those used to examine the conjunctiva, cornea and the tear device, such as fluorescein and cane rose; and (c) those used to examine abnormal pupillary responses, such as methacholine, cocaine, adrenaline, atropí72 698

16813 (AP) -Portugal

na, hydroxyamphetamine and pilocarpine (13) ophthalmic agents used as adjuvants in surgery such as alphaaquimotripsin and hyaluronidase;

(14) chelating agents such as ethylenediamine tetraacetate (EDTA) and deferoxamine :;

(15) immunosuppressive and anti-metabolite agents such as methotrexate, cyclophosphamide., 6-mercaptopurine and azathioprine;

(16) peptides and proteins such as natriuretic auricular factor, factor related to the calcitonin gene, lutiriizing hormone, release hormone, neurotyrisin, vasoactive intestinal peptide, vasopressin, cyclospore, interferon, substance P-encephalins, epidermal growth factor, growth factor derived from the eye, fibronectyria, insulin-like growth factor and mesodermal growth factor (17) lubricating agents such as sodium hyaluronate or poly (vinyl alcohol); and (18) combinations of the above agents such as antibiotics / anti-inflammatories as in neomycin sulfate / dexamethasone phosphate and sodium, concomitant anti-glaucoma therapy as in timolol / aceclidine maleate.,

Those skilled in the art will consider the above list of pharmaceutical compounds for example only. As the drug delivery compositions of the present invention are extremely well suited for use in a wide variety of physiological applications such as the ocular, oral, nasal, rectal or subcutaneous administration of pharmaceutical compounds, a wide variety of drugs can be incorporated into them. pharmaceutical agents. Thus, the foregoing list of pharmaceutical agents is not intended to limit the scope of the present invention and serves only as an example.

Preferably, when used as aqueous drug delivery vehicles for drop instillation, oral administration or injection, the compositions of the present invention can be modified to include from about 0.0001% to 50% by weight of pharmaceutical drugs or diagnostic agents.

To prepare an aqueous drug delivery vehicle.

69ί5

16813 (AP) -By tuga1 according to the teachings of the present invention, an appropriately effective amount of the chosen pharmaceutical compound is simply incorporated into the aqueous composition at the temperatures and pH of the composition formulation. Preferably, the chosen compound will be soluble in the solution or dispersed homogeneously and will not react with the polymer system. The soluble pharmaceutical compounds will be easily dissolved in the aqueous composition, while insoluble compounds will preferably be reduced to particles for uniform dispersion throughout the composition. In this vein, it is considered within the scope of the present invention to incorporate drug delivery systems into insoluble or erodible microparticles in aqueous compositions, such as those already known in the art. In this way, controlled release drug delivery systems can be incorporated into the aqueous compositions of the present invention and held in position when administered in drops or by injection.

After gelation, the medication or diagnostic agent.

it will be incorporated in the gelified matrix of the polymer and will remain in place for delayed action, since the solidified gel slowly wears out and the pharmaceutical agent is incorporated into the surrounding tear or physiological fluid. Note also that, by varying the concentration of the pharmaceutical compound in the aqueous composition, it is possible to modify and control the amount of pharmaceutical compound applied by drops or injection. For example, the liquid drug application vehicle can be prepared according to with the studies of the present invention from about 0.01 to about 5% of the drug or pharmaceutical agent chosen on a weight by weight basis. For drop instillation methodologies, the size of the drops should preferably vary from about 20 μΐ to 50 μΐ, with 25 μΐ drops being particularly preferred. Thus, from a drop of the liquid composition containing about 25 μΐ of solution, about 0.0025 mg to about 1.25 mg of drug can be obtained.

The following being illustrative of this invention ..

non-limiting examples are presented as the properties of the example compositions in the following example, the concentrations expressed

are weight percent (% w / w), deionized water is used to make the formulations and the temperature of the formulations and * C „

EXAMPLE 1

30 g of water was heated to about 90 ° C. To this heated water, 3 g of Methocel A4M (marketed by Dow Chemicals, Midland, MI) was added and the mixture was stirred until the polymer particles were completely wet and evenly dispersed. 67 g of cold water were added. to lower the dispersion temperature to about 10 ° C for complete solubilization. The final mixture was brought to 100 g of total weight by the addition of deionized water to obtain a mixture of 3% w / w Methocel. The resulting mixture was stirred for 2 h at 2.5 rpm.

In a separate container, 0.9 g of Carboxypolymethylene (marketed by B „F 940) was completely

Goodrich, Cleveland, 0H, as Carbopol dispersed and stirred in 90 g of deionized water. The mixture was stirred at 100 rpm for 2 h, after which water was added to bring the weight of the final mixture to 100 g s at a content of 0.9% w / w in Carbopol.

A physical mixture of 20 g of the 3% w / w solution of Methocel (prepared as above) and 20 g of the 0.9% w / w solution of Carbopol was prepared. 0.06 g of Levobunolol was dissolved in 18 g of deionized water and added to the physical polymer mixture. The resulting aqueous solution, containing the drug, was then titrated with 5N NaOH to pH 4.5 and the final formulation was brought up to 60 g by the addition of deionized water. The resulting formulation was as follows: 1% Methocel, 0.3% Carbopol and 0.1% Levobunolol .. Viscosity was measured using a Carri-Med Rheometer and a rheogram was obtained representing the shear stress vs shear rate The formulation had a viscosity of 12,000 cP to one of 2.64 / s. The mixture was a liquid that drained from the good characteristics for the water. drops production.

cut rate lightly with

EXAMPLE ii

The 3% w / w Methocel A4M mixture was prepared as established 72 698

16813 (AP) -Po rtu ga1

As in Example I, 40 g of this solution was mixed with 0.12 g of Carbopol 940, 0.6 g of Levobunolol and 18 g of deionized water „The mixture was then stirred at 50 rpm at room temperature for 15 h »The resulting mixture containing the drug was titrated with 5N NaOH to pH 4.2, then deionized water was added to bring the weight of the final formulation up to 100% (60 g) and stirred at 50 rpm for an additional 2 h. The final formulation obtained was as follows: 2% Methocel, 0.2% Carbopol and 0.1% Levobunolol. The viscosity was measured with a Carri-Med Rheometer and a reogram was obtained representing the shear stress vs shear rate, The formulation had a viscosity of 7 806 cP at a shear rate of 2.64 / s. The mixture was a smooth flowing liquid with good droplet characteristics.

EXAMPLE III

The 3% w / w Methocel A4M mixture was prepared, as set out in Example 1, A premixture of 0.06 g of salt (sodium chloride) and 0.06 g of Levobunolol was prepared, 40 g of Methocel solution with 0.18 g of Carbopol 940, with the premix of salt and Levobunolol and 16 g of water. The mixture was then stirred at 50 rpm for 15 h and then titrated with 5N NaOH to pH 4.0. The final formulation was made up to 100% by weight (60 g) by adding deionized water and stirred at 50 rpm for another 2 h „The final formulation obtained was as follows: 2% Methocel, 0.3% Carbopol, 0.1% sodium chloride and 0.1% Levobunolol» The viscosity was measured with a Carri-Med Rheometer and obtained a reogram representing the shear stress vs shear rate, The formulation had a viscosity of 8 3.17 cP at a shear rate of 2.65 / s. The mixture was a smooth flowing liquid with good characteristics for production of drops »

EXAMPLE IV

The 3% w / w Methocel A4M mixture was prepared, as set out in Example I, A pre-mixture of 0.06 g of Levobunolol and 0.18 g of Carbopol 940 was prepared, A mixture was prepared physics of 20 g of. 3% w / w Methocel solution with the prepared premix, followed by the addition of 38 g of deionized water. The mixture was stirred for 15 h at 50 rpm to ensure a

698

16813 (AP) -Portugal

complete mix

The resulting aqueous solution.

™ ·· _{; í} JSfX containing the drug.

it was then titrated with NaOH SM until pH 4.12 after which the final formulation was brought up to 60 g by the addition of deionized water, and then mixed for 2 h at 50 rpm. The resulting formulation was a. following: 1% Methocel, 0.3% Carbopol and u., 1% Levobunolol. The viscosity of the formulation was measured with a Carri-Med rheometer and a rheogram was obtained representing the shear stress vs shear rate. The formulation had a viscosity of 3 154 cP at a cut-off rate of 2., 55 / s „The mixture was a liquid that flowed smoothly and had good characteristics for the production of drops

EXAMPLE V

30 g of water was heated to 90¾. To this heated water, 5 g of Methocel A4M (sold by Dow Chemicals, Midland, Ml) was added and the mixture was stirred until the polymer particles were completely wet and uniformly scattered. The rest of the water, 67 g, was added as cold water to lower the dispersion temperature to about 10 ° C in order to complete the solubilization. The final mixture was brought to .100 g of total weight by adding purified water, to obtain a mixture of 5% w / w Methocel »The resulting mixture was stirred for 2 h at 25 rpm»

20 g of deionized water were weighed and 0.12 g of Carbopol 940 (marketed by BF Goodrich) was added. The solution was stirred at 50 rpm for 2 h until all of the Carbopol dispersed in the solution » To the Carbopol solution, 36 g of 5% Methocel solution, prepared as above, were added and 0.09 g of sodium chloride was added. ”The physical mixture was stirred for 12 h at 50 rpm to ensure complete mixing and dispersion. of the polymers. The mixture was then titrated with 5N NaOH to pH 3.53 and the final formulation was brought to 100% by weight. The final formulation by weight was: 3% Methocel, 0.2% Carbopol, 0.15% sodium chloride »The viscosity of the formulation was measured with a Carri-Med Rheometer and a rheogram was obtained representing the shear stress vs cut rate »The formulation had a viscosity of 16 610 cP at a cut rate of 2.64 / s. The mixture was a liquid that flowed smoothly and had good characteristics for the production of

696

16813 (AP) -Portugal drops.,

EXAMPLE VI

The 5% w / w Methocel A4M mixture was prepared as set out in Example V »A pre-mixture of 0.12 g of Carbopol 940 and 0.14 g of sodium chloride was prepared» 3 -mixture

g of water »The mixture was stirred at 50 rpm for 15 h and then titrated with 5N NaOH to pH 3.5» The final formulation was brought to 100% by weight by adding deionized water and stirred for more 2 h at 50 rpm »The final formulation» in weight percentage, was: 3% Methocel, 0.2% Carbopol, 0.25% sodium chloride »The viscosity was measured with a Carri-Med Reometer and a rheogram representing shear stress vs shear rate »The formulation had a viscosity of 16,600 cP at a shear rate of 2.85 / s» The mixture was a smooth flowing liquid with good characteristics for the production of drops »

EXAMPLE VII

A 3% Methocel A4M: w / w mixture was prepared as in Example I »0.12 g of Carbopol 940 (marketed by E» Goodrich) was dispersed in 16 g of deionized water »After dispersion was completed , 0.09 g of sodium chloride was added to this Carbopol solution and the resulting mixture was stirred at 50 rpm for 10 h. ”Then 40 g of 3% Methocel was added to the Carbopol / salt solution and stirred. mix for 4 h. The resulting mixture was then titrated with 5N NaOH to pH 4.49, after which deionized water was added to bring the final formulation to 100% by weight (60 g). „The final formulation, in percentage by weight, was ;. ^: 2% Methocel, 0.2% Carbopol, 0.15% sodium chloride »Viscosity was measured with a Carri-Med rheometer and a rheogram was obtained representing the shear stress vs shear rate» The formulation had a viscosity of about 11,500 cP at a cut rate of 2.64 / sec »The mixture was a liquid that flowed smoothly, with good characteristics for the production of drops»

698

16813 (AP) -Portugal

EXAMPLE VIII

An aqueous mixture of gol example was prepared, containing 3% Methocel A4M, 0.3% d © Carbopol 940 and 0.2% salt, with a load of 1% Acid Orange 8 dye for a kinetic study in vitro release. A 0.4 g sample of solidified gel of this composition was placed in a USP dissolution vessel (paddle speed 50 rpm) containing 500 ml of phosphate buffer at pH 7.4 and 37 ° C. The gel dissolution time was found to exceed 9 h. A T value of about 55 minutes and a Τφθ value of about 200 minutes were obtained from the gel dye release profile.

EXAMPLE IX

An analysis of the in ..... retention time of the gel was performed using rabbit eyes. The gel mixture of Example I was labeled with high molecular weight EITC dextran (MM approximately 70,000). Gel formation after instillation of a 50 μ gota drop appeared to be quite rapid and caused a continuous coating to form on the pre-corneal surface of the eye by the gel matrix. Photographic and biomicroscopic evaluations were obtained over a period of 7 hours of observation. There were two significant retention times of the delivery vehicle in the rabbit's eye: (1) a distinct gelatinous formation in the lower corner of the eye; and (2) a smooth, apparently uniform film on the ocular surface. The distinct gel formation lasted for about 3 h, while the uniform film retention time was 0 to 6.5 h or more.

EXAMPLE X

Sodium fluorescein was used as a marker for the composition of Example 2 to control its penetration into the anterior chamber of the eye. The anterior chamber of the rabbit's eye was controlled using the slit lamp technique and an increase in fluorescence increase was observed over a period of 7 h after instillation of the fluorescein-labeled gel72 698

16813 (AP) -Portugal

-28EXAMPLE XI

Research studies of acute toxicology do not reveal any signs of toxicity. No irritation, congestion, spots or cytotoxicity were observed with the use of the gel mixture in rabbit eyes. The eye condition was found to be healthy 24 hours after application.

EXAMPLE XII

An example drug delivery vehicle was prepared by incorporating drugs, in the following manner, into erodible microparticles in delivery vehicles. Levobunolol was mixed in a heated poly (orthoester) slurry and the mixture was cooled to solidify it. The drug containing poly (orthoester) was ground to give microparticles from 1 to 300 µm in size. These particles were physically dispersed in the example, reversible gelation composition described in Example I, obtaining a drug distribution, reversible geification, which incorporates microparticles containing erodible drug.

EXAMPLE XIII

An example therapeutic agent was prepared, for the treatment of keratoconj un txvite (Keratoconj un ti νítis sicca), from an aqueous composition containing 1% by weight of Methocel, 0.3% by weight of Carbopol 940 and 0.1 % by weight of sodium hyaluronate & isotonically adjusted with glycerol to pH 4.5-5.5. After applying a 50 μ drop to a rabbit's eye, an almost instantaneous gelation was observed. Examination of the rabbit eye 2.4 h after application indicated healthy eye status.

Those skilled in the art will appreciate that, although the foregoing examples are primarily directed to delivery vehicles for ophthalmic drugs, softening agents and topical compositions, it is intended that it is within the scope of the present invention to use the aqueous compositions of the present invention as vehicles. of drug delivery that can be administered orally or injected subcutaneously or 'intramuscularly' After injection of the freely flowing drug delivery vehicle, the aqueous composition will gel quickly

698

X 6 8X 3 (AΡ) -Portugal '29 “

- r '

IMMINALLY forming a stable deposit of drug distribution, from which the incorporated pharmaceutical compound can diffuse.,

However, it is preferred that the aqueous compositions of the present invention are used to deliver the pharmaceutical compounds to the surface of the eye. The pharmaceutical compounds can therefore be retained in contact with the surface of the eye over a long period of time to increase the bioavailability of the incorporated pharmaceutical compound. Such a drug delivery process would comprise the steps of preparing the aqueous composition of the present invention, containing the above-described effective amount of pharmaceutical compound, and introducing the composition into the tear secretions of the eye. Once introduced into the corner of the eye, the composition gels quickly and resists the dilution and depletion normally associated with the overflow of tears in the eye. The mucoadhesive gel thus formed remains in the eye for a significant period of time, slowly eroding and releasing the pharmaceutical agent dissolved in it. This prolonged residence time leads to more effective levels of the concentration of the pharmaceutical agent in the tear film and may in fact result in a decrease in the overall dosage that needs to be administered.

If the preferred exemplary embodiments of the present invention are thus described, those skilled in the art should note that the results set forth herein are examples only and that alternatives, adaptations and modifications are possible within the scope of the present invention. Thus, by way of example and not by way of limitation, it is considered that gelation polymers sensitive to ionic strength can also be used, as they become thick when exposed to variations in ionic strength. therefore, it is not limited to the present embodiments.

Claims (22)

1 - Process for the preparation of an aqueous composition of material that exhibits the property of reversibly gelling in response to substantially simultaneous variations in temperature and pH within predetermined ranges, characterized by combining or mixing at least one temperature-sensitive gelling polymer and at least a pH-sensitive gelling polymer, in order to obtain an aqueous composition of material having from 0.1% to 30% by weight of said temperature-sensitive gelling polymer and from 0.01% to 10% by weight of said polymer pH sensitive gelling agent, Process according to claim 1, characterized in that said aqueous material composition comprises an effective modifying concentration of. reversible viscosity, a stable combination of at least one temperature sensitive gelling polymer and at least one pH sensitive gelling polymer, Process according to claim 1, characterized in that said at least one temperature sensitive gelling polymer is selected from the group consisting of alkyl cellulose, hydroxyalkyl cellulose, Pluronic polymers ^ and Tetronic polymers ^ „ Process according to claim 1, characterized in that said at least one temperature sensitive gelling polymer is methyl cellulose, Process according to claim 1, characterized in that said at least one pH-sensitive gelling polymer is an acidic polymer, Process according to claim 5, characterized in that said acidic polymer is a carboxyl-containing polymer. 7 - Process according to claim 6, characterized 72 698 16813 (AP) -Portugal -31 ”in that said carboxyl-containing polymer is polyacrylate» Process according to claim 2, characterized in that said at least one temperature sensitive gelling polymer is methyl cellulose and said at least one pH sensitive gelling polymer is polyacrylate » Process according to claim 8, characterized in that said aqueous solution comprises approximately 0.1% to 5% by weight of methyl cellulose and approximately 0.01 to 10% of polyacrylic. broad » Process according to claim 8, characterized in that said aqueous solution comprises approximately 1% by weight of methyl cellulose and approximately 3%; by weight of polyacrylate » Process according to claim 1, characterized in that it also includes a quantity of salt, which modifies the viscosity » Process according to claim 11, characterized in that said salt is selected from the group consisting of dissociable, univalent or divalent ionic compounds » Process according to claim 12, characterized in that said salt is present in a salt / polymer ratio of approximately 0.001 to 0.5 » Process according to claim 1, characterized in that said range of temperature variation is approximately 0 ° to 60 ”C» Process according to claim 1, characterized in that said range of pH variation is approximately 2.5 to 7.4 » 16 - Process according to claim 2, featuring 72 698 16813 (AP) -Po rtuga1 ............. · ·. ·; · * · Since it also comprises, mixing or combining with the said aqueous composition of material, approximately 0.0001% to 50% by weight of a pharmaceutical medicine or diagnostic compound. Process according to claim 16, characterized in that said pharmaceutical medicine or diagnostic compound is incorporated into a microparticulate drug delivery system. Process according to claim 16, characterized in that said pharmaceutical medication or diagnostic compound is selected from the group consisting of anti-bacterial substances, antihistamines and decongestant compounds, anti-inflammatory, myotics and anti-cholinergics, hydrolytics , anti-glaucoma, ariti-parasitic and anti-viral compounds, carbonic anhydrase inhibitors, diagnostic agents, ophthalmic agents, chelating agents, immunosuppressive agents, ariti-metabolites, anesthetic and antifungal compounds, amibicidal compounds, agents trichomonicides, analgesic agents, anti-arthritic, arithmetic, anti-coagulants, anti-convulsions. vantes, antidepressants, antidiabetics, antineoplastics, antipsychetics, antihypertensives, muscle relaxants, proteins, peptides and lubricating agents. 19. The method of claim 16, wherein said aqueous material composition is an ophthalmic drug delivery system and comprises an effective amount of an ophthalmic drug. Process according to claim 19, characterized in that said ophthalmic drug is incorporated into a microparticulate drug delivery system. Process according to claim 20, characterized in that said ophthalmic drug is selected from the group consisting of anti-bacterial substances, antihistamines and decongestant, anti-inflammatory, myotic and arithmetic compounds. 698 16813 <AP) -Portugal -cholinergics, mydriatics, anti-glaucoma compounds, anti-parasitic or anti-viral compounds, carbonic anhydrase inhibitors, diagnostic agents, ophthalmic agents, chelating agents, immunosuppressive agents, anti-metabolites, anesthetic and anti- fungicides, amibicidal compounds, trichomonic agents, analgesic agents, anti-arthritic, anti-asthmatic, anti-coagulant, anti-convulsant, anti-depressant, anti-diabetic, anti-neoplastic, arithypsychotic, anti-hypertensive, muscle relaxant agents , proteins, peptides and lubricating agents, Process according to claim 16, characterized in that said aqueous composition of matter is an injectable drug-releasing composition for injection into a body, to treat a situation that requires pharmacological or diagnostic treatment, said pharmaceutical being or diagnostic compound selected from the group consisting of anti-bacterial substances, anti-histamines and decongestant, anti-inflammatory, myotics and aryti-cholinergic, mydriatic, anti-glaucoma, anti-parasitic and anti-viral compounds, carbonic anhydrase inhibitors, diagnostic agents, ophthalmic agents, chelating agents, mucosuppressive agents, anti-metabolites, anesthetic and anti-fungal compounds, amibicidal compounds, trichomonic agents, analgesic, anti-arthritic, anti-asthmatic, anti-coagularite agents, anti -convulsants, anti-depressants, anti-diabetics, anti-neoplastics, anti-psychotics cos, antihypertensives, muscle relaxants, proteins, peptides and lubricating agents.